Pathology

Premalignant and Malignant Neoplasms.

Objectives:

After completing this tutorial the student will be able to:

• classify the premalignant conditions and malignant neoplasms of the vulva
• describe their epidemiologic features
• describe their clinical features
• describe/recognize histologic features and grade various lesions
• determine clinical behavior and outcome

1. Vulvar Intraepithelial Neoplasia — VIN ("Dysplasia")

VIN represents a spectrum of neoplastic changes in the vulvar epithelium that range from mild cellular dysplasia to the most severe cellular changes that fall short of invasive carcinoma. It is a precursor lesion of vulvar squamous cell carcinoma.

• Epidemiology.

  The lesion occurs in elderly women, but is becoming increasingly common in young women between 20 and 35 years old. Most cases (about 90%) are associated with HPV, especially types 16, 18 and other high-risk types.

• Clinical presentation.

VIN presents as a white, red, or hyperpigmented indistinct macular lesion or well-defined raised plaque, which may be single or multiple. It is frequently multifocal with associated lesions in the cervix (more often) or the vagina.

Note white flat patches and plaques.

Question: What benign lesions of the vulva may be clinically confused with VIN?

• Histology

Both architectural and cytologic abnormalities are present. The normal progression of cell maturation within the vulvar squamous epithelium from basal layer to surface is lost (loss of polarity). Cytologic abnormalities are in the form of dysplastic cells with nuclear hyperchromasia and showing variation in shape and size (cellular pleomorphism). Some may have appearances of undifferentiated, basaloid cells, while others may show evidence of single cell keratinization (dyskeratosis). There is increase in the number of mitotic figures with mitosis present above the basal layer. Abnormal mitoses may also be seen.

NOTE: Although the lesion is associated with HPV infection koilocytes are rarely present.

There is hyperkeratosis, and dysplastic cells with nuclear hyperchromasia and pleomorphism are present. Mitoses (in circles) are seen above the basal layer.

• Grading

The number and distribution of dysplastic cells vary considerably within the thickness of the squamous epithelium reflecting the varying severity of the condition. A convention to grade the severity of VIN has therefore been developed This is based on the proportion of the total thickness of the epithelium replaced by dysplastic cells and is done in thirds of the total thickness of the epithelium involved.

• VIN 1: Mild; dysplastic cells are confined to the lower third of the epithelium.
• VIN 2; Moderate; dysplastic cells occupy up to the lower two thirds of the epithelium
• VIN 3; Severe, carcinoma-in-situ; dysplastic cells extend into the upper third of the epithelium. Carcinoma-in-situ may be used when dysplastic cells occupy the full thickness of the epithelium and the underlying stroma has not been invaded.

• Clinical behavior

The lesion may regress spontaneously, recur after local excision, or progress to invasive squamous cell carcinoma if untreated (10% of cases). The risk of progression to invasive carcinoma increases with age and in immunosuppressed women.

2. Invasive squamous cell carcinoma

• Epidemiology

Squamous cell carcinoma is the commonest malignant tumor of the vulva, representing about 95% of all vulvar malignancies. Risk factors include cigarette smoking, number of sexual partners, and chronic granulomatous disease. Vulvar squamous cell carcinomas may be divided into two general "types":

The first type affects older women and not related to HPV

The second type affects younger women and related to HPV

• Clinical appearance

The lesion begins as an area of induration but progresses to form an exophytic mass or an endophytic ulcer with raised, everted edges. The labia are the most common location (90% - labia majora more than minora; clitoris 10%).

Ulcerated endophytic tumor with raised everted edges.

• Histology

Microscopically, most squamous cell carcinomas of the vulva are well differentiated with keratinization. Poorly differentiated tumors are uncommon. Associated VIN may be present at the margins.

Well differentiated squamous cell carcinoma. Nests of tumor cells, some with keratin pearls, are present.

• Clinical behavior

The tumors grow slowly and extend to the contiguous skin, invade deeply to involve the vagina and rectum and metastasize to regional lymph nodes. The outcome depends on stage, especially regional node status. Overall 5-year survival of treated patients is 50% for positive nodes and 75% for negative nodes.

Question: Which clinical features determine the risk of metastatic spread of vulvar squamous cell carcinoma?

3. Superficial invasive squamous cell carcinoma

This is defined as squamous cell carcinoma that measures less than 2 cm in diameter, invades to a depth less than 1 mm and shows no lymphovascular invasion.

The importance of these tumors is that they show a decreased risk of spread to regional lymph nodes and therefore have better prognosis than more deeply invasive tumors. The overall 5-year survival is greater than 90%.

4. Extramammary Paget’s disease

• Clinical appearance.

This is a rare disease of the vulva, which affects predominantly post-menopausal women. The lesion usually occurs on the labia majora and presents as an erythematous (red), sharply demarcated area. It is itchy or may give rise to a burning sensation. It may be single or multicentric and may involve the perianal region. The microscopic extent of the disease is often greater than is clinically detectable.

Vulvar Paget’s disease. Note erythematous lesion on left labium majus.

• Histology

Microscopically, the lesion is identified by the presence of large, pale, mucin-containing epithelial cells scattered singly or in small nests within the epidermis. It is associated with an underlying invasive adenocarcinoma in 20% of cases.

Vulvar Paget’s disease. Tumor cells with abundant pale cytoplasm infiltrate the epidermis individually and in nests.

• Clinical behavior.

Untreated, vulvar Paget’s disease runs a slowly progressive, indolent course. Recurrence after treatment is not uncommon due to inadequate excision (note that microscopic extent often exceeds clinically visible margins) or multicentricity. Metastases do not occur if the disease remains in situ (i.e. within the epidermis). Prognosis depends on whether there is an associated invasive tumor.

Question: Which other parts of the body may similar lesions occur?